Bisphosphonates are well known chemical compounds used in medicine for the prevention or treatment of several metabolic diseases of the bone, e.g. metabolic osteopathies, such as osteoporosis, cancer metastasis and the osteopathies associated with rheumatoid arthritis.
Bisphosphonates can be prepared using various methods already described in the literature through which different crystalline species can be obtained. A selection of known bisphosphonates is presented in the following scheme.

Bisphosphonates may exist in the form of acids, salts, hydrates and amino-derivatives.
Monosodium alendronate, for example, may be prepared according to the Argentinean Patent AR 000.052.
Pamidronate and olpadronate are other bisphosphonic derivatives which contain one nitrogen in the lateral chain. Olpadronate is the naturally most soluble compound in the group of bisphosphonates and may be synthesized according to the Argentinean Patent AR 246.743 and EP 0 891979 AI, whereas the synthesis of pamidronate is disclosed in the Argentinean Patent AR 218.558.
The amino-derivatives of bisphosphonates may be synthesised according to the methods stated in WO 97/02827 and AR 004.625.
Further synthetic routes to obtain pamidronate are disclosed in U.S. Pat. No. 3,962,432, further describing tablets, capsules, tooth-pastes and mouthwash containing pamidronate. U.S. Pat. No. 4,407,761 and U.S. Pat. No. 4,639,338 claim certain crystalline forms of pamidronate suitable for injectable solutions or pills, tablets, capsules and suppositories.
U.S. Pat. No. 4,446,052 discloses aqueous gels of tricalcic pamidronate to be administered in capsules or tooth-pastes, aimed at dissolving calcareous deposits.
Alendronate is a derivative of bisphosphonates known since the 1970's and a method for its synthesis is for example disclosed in U.S. Pat. No. 4,621,077, further disclosing general formulations of capsules, effervescent granules and injectable solutions. EP 402152 refers to trihydrate alendronate.
U.S. Pat. No. 5,462,932 discloses specific liquid oral formulations containing alendronate for facilitating deglutition in people who have difficulties in swallowing. The formulations of U.S. Pat. No. 5,462,932 are based on the presence of EDTA as stabilising agent and/or the presence of citric acid as buffer agent. Special stabilizers were deemed to be essential in the formulations of bisphosphonates.
EP 336851 discloses tablets of several types of bisphosphonates that contain sodium laurylsulphate as excipient which is well known for persons skilled in the art. Other bisphosphonates, such as ibandronate, are described in U.S. Pat. Nos. 4,927,814 and 4,942,157.
Among the several medical indications presented by the bisphosphonates, the use in the prevention and treatment of established osteoporosis, see Papapoulos S. E. et al., The use of bisphosphonates in the treatment of osteoporosis, Bone 1992, 13: A41-A49A the treatment of bone metastases of cancer, see van Holten-Verzantvoort A. et. al., Oral pamidronate in the prevention and treatment of skeletal metastases in patients with breast cancer, Medicina (Buenos Aires), 1997, 57 (suppl.): 109-113; and the osteopathies associated with rheumatoid arthritis, see Maccagno A. et al., Double blind radiological assessment of continuous oral pamidronic acid in patients with rheumatoid arthritis, Scan J Rheumatol, 1994, 23:211-214, are highlighted.
All these medicinal uses imply the continuous/pulse administration of the bisphosphonate for long periods—5 or more years. Thus, the use of preparations suitable for oral administration is preferred.
“Continuous or pulse use” is understood as the use that fosters an inhibition of bone metabolism in a smooth and constant way, as proved by the steady levels curve of the markers of bone metabolism.
On the other hand, there is the non-continuous or cyclical use of bisphosphonates, stimulating a stronger depression of bone metabolism, followed by a tendency to cover basal level. With this modality, the biochemical markers curve thus fluctuates with troughs and peaks, demarcated by each cycle of administration.
In the continuous mode, each administration of bisphosphonates can be referred to as a pulse, see Roldan E J A et al, Clinical evaluation of bisphosphonates pharmacokinetics principles, Medicine (Buenos Aires), 1997, 57 (suppl.):76-82.
While daily, weekly of half-weekly pulses foster a continuous metabolic change in the bone, monthly, bimonthly or three-monthly pulses foster a metabolic discontinuous or cyclical change.
While no exact definition of the limit between cyclical and continuous modalities is known, the present invention is aimed at improving the pulse administration of bisphosphonates.
The “pulse” concept for bisphosphonate administration has also been common clinical practice in patient with small body mass, in children, and in those who do not tolerate daily administrations, see Roldan E J A et al, J Pediat Endocrinol Metab 1999, 12:555-559.
Up to now, however, the requirement of high doses of bisphosphonates has hindered a successful oral administration, especially due to potential problems of digestive tolerance. Moreover, most bisphosphonates have a very low solubility, 3% v/v or less. This favours a very low absorption of the compound, that means a bioavailability of at best 1%. Therefore, 99% of the remaining active substance may easily form lumps and precipitate in the digestive lumen which can result in digestive irritability. Symptoms resulting from such irritability may range from unspecified discomfort to pain, vomit and as well as esophagitis and gastritis.
Lesions in the digestive system can be related to the intrinsic potential of the dissolution of the pharmaceutical form and to the quantity of molecules administered each time, see Spivacow R. S. et al, Tolerability of oral bisphosphonates in patients with osteoporosis and other osteopathies, Medicina (Buenos Aires), 1997, 57(suppl.): 114-118.
Attempts have been made in the prior art to improve tolerability by prescribing doses low in bisphosphonates under very strict conditions, taking the bisphosphonate at least 30-60 minutes before breakfast with abundant water. Moreover, the patient must keep a strict fast and must remain standing or sitting during all the pre-breakfast period. Of course, these rigid instructions are bothersome and, together with side effects, may lead to the non-observance of the prescriptions. The patient finds little incentive to go on with an uncomfortable administration plan that disturbs the habitual rhythm of life and that, in most cases aims at preventing an uncertain fact, such as the probability of fractures due to osteoporosis in old age. Often, a short time after beginning treatment, the patient gives up the observation of the instructions and failures and side effects associated to poor fulfillment of the prescription appear.
Therefore, it is an object of the present invention to overcome the drawbacks of the prior art, especially to provide a composition for prevention, treatment and/or diagnosis of metabolic diseases of bones which would enable a more comfortable administration of bisphosphonates, in order to make possible a strict fulfillment of the prescriptions and long-term clinical effects. Moreover, it is a further object of the invention to lessen a risk factor of toxicity that is represented by the lumps resulting from the break-up of oral forms.
Moreover, it is a further object of the present invention to provide a process for preparing a composition according to the invention and to allow the use of such a composition for the prevention, treatment and/or diagnosis of metabolic diseases of bones.